T1D & comorbidities

Beyond HbA1c—How Are We Managing Type 1 Diabetes Comorbidities?

Presented by:
Petter Bjornstad, MD
Assistant Professor, Pediatric Endocrinology
University of Colorado School of Medicine, Aurora, CO; USA

There are a number of complications, comorbidities, and causes of mortality associated with type 1 diabetes patients. While intensive glucose control reduces the mortality risk, people with type 1 diabetes have an 8-13-year lifespan shorter than the general population. In addition, reaching a target HbA1c of <7% does not abolish risk. Lastly, cardiovascular disease remains a leading cause of mortality in this population.1,2 Questions still remain as to whether more aggressive treatment, with more attention to secondary prevention, will lead to better outcomes.3 It is time to focus on other areas aside from HbA1c, such as renin-angiotensin-aldosterone system inhibitors (RAASi)/SGLT1/2 inhibitors, statins, and metformin for hypertension/diabetic kidney disease and dyslipidemia, respectively, to determine the effect of treatment on these patients.3

In the Heart Protection Study, a trial that enrolled almost ,6000 patients with both type 1 and type 2 diabetes, patients were treated with simvastatin vs. placebo.4 Patient data were reviewed per diabetes type and found limited benefits of reducing the first vascular event (major coronary event, stroke, or revascularization) in patients with type 1 diabetes compared to those with type 2 diabetes.4 Similar results were found in a meta-analysis of 26 trials (170,000 participants) where patients with type 1 diabetes did not show as much reduction in cardiovascular disease (CVD) and LDL-cholesterol as those with type 2 diabetes when taking a statin.5 In a propensity score matched review of the Swedish National Diabetes Registry (n = 4,025), statin therapy did not have an effect on CVD or rate of death in patients with type 1 diabetes.6 ACE inhibitors have also shown minimal effect in type 1 diabetes patients.7

A study using RAASi in patients with type 1 diabetes demonstrated no statistical significant advantage from using RAASi vs. placebo in mesangial fractional volume or mesangial matrix fractional volume.8 There was an increase in microalbuminuria with losartan use, and minimal changes (not significant) with placebo and enalapril.8 Glomerular filtration rate values remained consistent within all 3 groups.8 Taken together, findings from this study suggest that the early blockade of the renin-angiotensin system in patients with type 1 diabetes does not slow the progression of nephropathy.8

Patients with type 1 diabetes can have a higher magnitude of insulin resistance compared to patients with type 2 diabetes.9 When reviewing the REMOVAL trial in type 1 diabetes patients treated with metformin, no statistically significant difference in the mean carotid intima-media thickness (cIMT) was observed in patients on metformin compared with those on placebo.10 However, a significant reduction was seen in the tertiary outcome, maximal cIMT in patients receiving metformin compared to placebo.10 When measuring HbA1c levels across visits in overweight/obese patients with type 1 diabetes on metformin + insulin, metformin did have an effect on total daily insulin dose, fat mass, and body mass index. No effect was seen in systolic/diastolic blood pressure or lipid values.11 The metformin EMERALD study demonstrated an improvement in insulin sensitivity in overweight/obese type 1 diabetes patients both per kilogram and kilogram-free fat mass.12 Findings were also beneficial in favor of metformin for endothelial dysfunction, as measured by maximum ascending aortic wall shear stress, and central arteriole stiffness, as measured by ascending aortic pulse wave velocity.12

The ATIRMA trial evaluated the use of SGLT2 inhibitors in patients with type 1 diabetes.13 In an 8-week open-label trial, empaglifozin appeared to reduce hyperfiltration, common in the early stages of diabetic nephropathy.13 A more recent study performed in 1,402 patients demonstrated the benefits of the SGLT1/2 inhibitor sotagloflozin in reducing systolic blood pressure, if compared to placebo. However, the risk for diabetic ketoacidosis was also increased with sotagliflozin.14

Key Messages

  • Benefit of statins on CVD in type 1 diabetes has been demonstrated in observational studies, but trials remain mostly negative.
  • RAAS inhibitors did not reduce cumulative incidence of albuminuria in youth or adults with type 1 diabetes.
  • Metformin improved insulin sensitivity and some markers of CVD, but data are inconsistent in type 1 diabetes.
  • SGLT2 and SGLT1/2 inhibitors lowered systolic blood pressure and attenuated hyperfiltration in adults with type 1 diabetes, but increased risk of euglycemic DKA.
  • There is a lot of room to improve CVD outcomes in type 1 diabetes.
  • Early intervention can have the greatest effect on prevention, and should go beyond A1c control.


Present disclosure: The presenter reported that he is a consultant for Boehringer Ingelheim and has participated on an advisory board for Horizon Pharma.

Written by: Debbie Anderson, PhD

Reviewed by: Marco Gallo, MD


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